Role of skeletal muscle in the epigenetic shaping of motor neuron fate choices

We study the role of muscle in the epigenetic (N.B., we use this term with the broader and more integrative meaning) shaping of developing motor neuron fate choices employing an approach based on mouse mutagenesis and pathology. The developmental role of skeletal muscle is studied in the whole mouse embryo by knocking out myogenic regulatory factors Myf5 and MyoD, to obtain an embryo without any skeletal musculature (Rudnicki et al., 1993). Our goal is to find muscle-provided trigger(s) of motor neuron death relevant to motor neuron diseases such as amyotrophic lateral sclerosis. The reason for this kind of thinking is the fact that a complete absence of lower and upper motor neurons, which is the pathological definition of amyotrophic lateral sclerosis, is only achieved in the complete absence of the muscle (Kablar and Rudnicki, 1999). Mutual embryonic inductive interactions between different tissue types and organs, between individual cell types belonging to the same or different lineages, and between various kinds of molecular players, are only some examples of the complex machinery that operates to connect genotype and phenotype. So far, our studies indicate that some aspects of this interplay can indeed be studied as proposed in this review article, suggesting the role of skeletal muscle in the epigenetic shaping of motor neuron fate choices. We will therefore continue this investigation as outlined to gain more insight into the nature of the epigenetic events that lead to the emergent properties of a phenotype.